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Development of Resistance to Intrinsic Apoptotic Stimuli in Lymphocytes without Alterations in Bcl‐2 Family Member Gene Expression
Author(s) -
Bortner Carl,
Scoltock Alyson,
Cidlowski John
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.569.4
Subject(s) - apoptosis , microbiology and biotechnology , biology , programmed cell death , intrinsic apoptosis , gene , population , gene expression , genetics , caspase , medicine , environmental health
Apoptosis is a physiological mode of cell death that removes unwanted cells at a specific time or in response to a given cell death signal. Apoptotic resistance is a common feature in many disease states that impedes the treatment of these pathologic conditions. We have developed a model system to investigate apoptotic resistance in T‐cells using osmotic stress to drive selection of death resistant cells. Exposure of S49 (Neo) cells to multiple rounds of osmotic stress which induces apoptosis, followed by recovery of surviving cells resulted in the production of a stable population of T‐cells (S49 (OS 4‐25)), resistant to acute osmotic stress and failed to die. These cells are also resistant to multiple intrinsic apoptotic stimuli. In contrast, S49 (OS 4‐25) cells remain sensitive to extrinsic apoptotic stimuli, suggesting the cellular apoptotic machinery remains intact. The S49 (OS 4‐25) cells undergo aerobic glycolysis, characteristic of the Warburg effect, and have a total dependence on glucose; whereupon its withdrawal results in apoptosis. Microarray analysis of S49 (OS 4‐25) compared to the parent S49 (Neo) cells revealed over 8,500 differentially regulated genes with almost 90% of the genes having repressed expression. Pathway analysis indicates apoptosis and mitochondrial dysfunction having major changes in gene expression. Interestingly, gene expression of pro‐ and/or anti‐apoptotic Bcl‐2 family members were either repressed or unchanged. Our findings implicate stimulus‐specific recognition defects and altered signaling mechanisms, but not specific pro/anti‐apoptotic Bcl‐2 proteins are critical determinants of apoptotic resistance in lymphoid cells.